Enantioselective preparation of optically pure albuterol

Abstract

The invention relates to a method for producing albuterol by the resolution of a mixture of enantiomers of 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate using ditoluoyltartaric acid.

What is claimed is: 
     
       1. A method for obtaining a single enantiomer of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate comprising the steps of: (a) dissolving a mixture of enantiomers of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate and a chiral acid selected from the group consisting of (-)-di-toluoyl-L-tartaric acid and (+)-di-toluoyl-D-tartaric acid in methanol by heating to form a solution;   (b) allowing said solution to cool, whereby a salt of primarily one stereoisomer crystallizes;   (c) separating said salt from said solution;   (d) recrystallizing said salt from methanol, whereby a diastereomeric salt having greater than 90% ee of an enantiomer of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate is obtained   (e) separating said diastereomeric salt from the methanol solvent; and   (f) liberating said enantiomer of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate from said diastereomeric salt by treatment with base.   
     
     
       2. A method according to claim 1 wherein said chiral acid is (-)-di-toluoyl-L-tartaric acid and said enantiomer of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate is the S enantiomer. 
     
     
       3. A method according to claim 1 wherein said chiral acid is (+)-di-toluoyl-D-tartaric acid and said enantiomer of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate is the R enantiomer. 
     
     
       4. A method for making optically pure albuterol comprising the steps of: (a) dissolving a mixture of enantiomers of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate and a chiral acid selected from the group consisting of (-)-di-toluoyl-L-tartaric acid and (+)-di-toluoyl-D-tartaric acid in methanol by heating to form a solution;   (b) allowing said solution to cool, whereby a salt of primarily one stereoisomer crystallizes;   (c) separating said salt from said solution;   (d) recrystallizing said salt from methanol, whereby a diastereomeric salt having greater than 90% ee of an enantiomer of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate is obtained;   (e) separating said diastereomeric salt from the methanol solvent;   (f) liberating the enantiomer of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate from said diastereomeric salt by treatment with base; and   (g) reducing said enantiomer of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate thereby forming optically active albuterol.   
     
     
       5. The method of claim 4 wherein said enantiomer of 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate is reduced with borane-methyl sulfide. 
     
     
       6. The method of claim 4 wherein said enantiomer of 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate is reduced with lithium aluminum hydride. 
     
     
       7. The method of claim 4 wherein said mixture of enantiomers of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate is obtained by the steps of: (a) reacting methyl 5-acetylsalicylate with hydrogen bromide in dimethyl sulfoxide, thereby forming a keto aldehyde;   (b) reacting said keto aldehyde with tert butylamine, thereby forming an α-iminoketone;   and   (c) reducing said α-iminoketone to provide methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate.   
     
     
       8. A method according to claim 7 wherein said α-iminoketone is reduced with a hydride reducing agent. 
     
     
       9. The method of claim 7 wherein said hydride reducing agent is selected from the group consisting of sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride. 
     
     
       10. A method according to claim 7 wherein said α-iminoketone is reduced by catalytic hydrogenation. 
     
     
       11. A method according to claim 10 wherein said catalytic hydrogenation is carried out over a heterogeneous noble-metal catalyst. 
     
     
       12. The method of claim 11 wherein said heterogeneous noble-metal catalyst is Pd/C. 
     
     
       13. The method of claim 11 wherein said heterogeneous noble-metal catalyst is Pt/C. 
     
     
       14. The method of claim 11 wherein said heterogeneous noble-metal catalyst is PtO 2 .